An early-phase tolerance to toxic doses of lipopolysaccharide (LPS) can be induced in mice by prior administration of sublethal doses of LPS or lipid A. These tolerant mice exhibit no hypothermia on subsequent administration of LPS and can survive a challenge dose of LPS that would normally be lethal. Peritoneal exudate cells of LPS-tolerant mice synthesized significantly reduced amounts of prostaglandins and of procoagulant activity (PCA) and tumor necrosis factor (TNF) when stimulated with LPS in vitro (compared to macrophages of control animals). Tolerance induction with lipid A was somewhat less effective. A regulatory mechanism of E-series prostaglandins (PGE) might be involved in the induction of hyporesponsiveness in macrophages of tolerant mice, as the LPS-stimulated TNF release could be inhibited in a dose dependent manner by preincubation with PGE1. Since PCA and TNF are mediators that are proposed to play a very important role in the pathophysiology of septic and endotoxic shock, a reduction in the release of these mediators may be partially responsible for early-phase tolerance to LPS.